The overall goal of this study is to identify the signaling mechanisms of the renal epithelial cell dedifferentiation that occurs following injury and during regeneration following acute renal failure (ARF). In contrast to the heart or brain, the kidney can recover from an ischemic or toxicant insult. During recovery, surviving tubular epithelial cells dedifferentiate, migrate, and proliferate, replacing the dead and lost epithelial cells and restoring tubular integrity. Although conversion of the epithelia to the dedifferentiated phenotype is a prerequisite for migration and proliferation in the recovery process, the factors and mechanisms responsible for the conversion have not been elucidated. Our preliminary data demonstrate that 1) after oxidant injury, surviving renal proximal tubular cells (RPTC) acquire a spindle-shape morphology and express vimentin, a marker of dedifferentiated epithelial cells; 2) p38 and the epidermal growth factor receptor (EGFR) are activated after oxidant injury to RPTC; 3) inhibition of p38 blocks EGFR phosphorylation; and 4) inactivation of EGFR or p38 blocked RPTC dedifferentiation. These observations have resulted in the hypothesis that p38-mediated activation of EGFR signaling after injury regulates RPTC dedifferentiation. Specific Aim 1 will define the role of p38 and EGFR in RPTC dedifferentiation in primary cultures of RPTC following oxidant and hypoxia/reoxygenation (H/R) injury. Specific Aim 2 will elucidate the mechanisms of p38-mediated regulation of EGFR activation following oxidant and H/R injury. Specific Aim 3 will determine the role of the E-cadherin/beta-catenin complex in transducing EGFR activation to RPTC dedifferentiation following oxidant and H/R injury. Specific Aim 4 will evaluate the role of p38 and EGFR in RPTC dedifferentiation in ischemia/reperfusion-induced ARF in mice. These studies will increase our knowledge of the mechanisms of RPTC dedifferentiation after injury and may contribute to the development of novel treatment for patients with ARF. [unreadable] [unreadable] [unreadable]